Sugar and Spice: Gender Bias Evident in Growth-Hormone Therapy

Becky McCall

June 22, 2015

Boys outnumber girls three to one for the treatment of idiopathic short stature (ISS) with growth hormone,finds a new study of the four US pediatric growth-hormone registries.

"This finding is true even though in a general pediatric population…equal proportions of both genders fall under the height threshold designating ISS [more than 2.25 standard deviations (SD) below mean growth for age and gender]," said lead author Dr Adda Grimberg (Children's Hospital of Philadelphia [CHOP], Pennsylvania) in an interview with Medscape Medical News.

Treatment and/or referral bias are the likely explanations as to why boys predominantly receive growth hormone, write Dr Grimberg and colleagues in their report, published online June 9 in Scientific Reports.

Dr Grimberg added: "In the absence of any confirmed medical explanation for short stature, psychosocial considerations play a greater role in the medical decision making."

Social pressure to be tall, at least in the United States, is stronger for males than females. "Taller males have a dating/mating advantage that taller females do not. Studies have associated tallness in males with markers of socioeconomic success," she noted.

And she emphasized that the treatment decision is shared between clinician and parents and that, "in considering the potential benefits and risks of treatment, these social pressures may tip the balance in favor of growth-hormone treatment for boys. It may be perceived as 'worth' the potential hassles, risks, and cost for boys but not for girls."

Asked to comment Dr Alan Rogol, professor emeritus of pediatrics and pharmacology, University of Virginia, Charlottesville, who has a special interest in growth and puberty, observed: "There is not an objective, scientific reason for this very real discrepancy between boys and girls. That's a fact. The rest is sociology.

"The reality is that little girls are considered cute, but a boy's self-esteem and self-worth are associated with being the 'warrior king' or similar."

Offering one potential explanation for the findings, Dr Rogol noted that the decision on using growth hormone is made at around 12 to 14 years of age, "when sports and girls are very important for boys, and one cannot compete in either if you are little and slight. So there's an emphasis that boys need to be bigger, and this enters the calculus about the importance of intervening.

"To me, intervening with growth hormone is reasonable in a small subset of children and adolescents with ISS, but it should be just as reasonable for girls as it is for boys."

Data From All Four US Growth-Hormone Registries

Previous analyses have shown that more boys than girls receive growth hormone in the United States and that the greatest gender difference is seen among those with ISS.

In their study, Dr Grimberg and colleagues set out to investigate whether this is due to a greater prevalence of growth impairment in boys or gender-based referral and/or treatment biases.

They examined the prevalence of short stature of unknown cause, (below the ISS threshold of 2.25 SD), by gender in 189,280 patients, aged 0.5 to 20 years, in a large, heterogeneous pediatric population from 28 regional primary-care practices.

These figures were then compared with treatment patterns in the four US growth-hormone registries.

Among children in the regional primary-care practices, a total of 2073 (1.1%) of boys and girls were below the Food and Drug Administration (FDA) criterion for ISS (−2.25 SD). But no difference was seen between boys and girls in prevalence of short stature: boys made up 51% of the ISS group (P = .35).

In contrast, in the registries, boys constituted 74% of growth-hormone recipients for ISS and 66% for all indications.

Decisions Around Treatment are Psychosocial

Most patients (of both genders) were started on growth-hormone treatment for ISS during puberty, and it was at this stage that the greatest gender difference in growth-hormone initiation occurred. Boys were found to outnumber girls (P < .05) at every age except the first year of growth-hormone initiation.

US pediatric endocrinologists see about twice as many boys as girls for evaluation of short stature, explain the authors, and surveys of hypothetical case scenarios show that they are more likely to give growth hormone to boys than girls.

Regarding the clinical approach to treating ISS, Dr Grimberg remarked: "For some children, all the clues suggest there is nothing wrong apart from short stature. In this category, the severity of the shortness and the problem(s) as perceived by the clinician and/or the family — influence who receives growth hormone treatment.

"Short stature, in and of itself, is not a disease. This gives psychosocial considerations more sway in influencing the medical decision making, and these considerations prompt growth-hormone treatment of more boys than girls," she added.

Efficacy of Growth Hormone in ISS is Unclear

And Dr Grimberg pointed out that the potential benefits and risks of growth-hormone therapy for ISS need to be carefully balanced.

"Patients with ISS already make sufficient growth hormone, so there are no additional benefits for metabolism of taking growth hormone, other than to augment height, and not all patients with ISS increase their height with growth-hormone supplementation."

She also noted that although growth hormone is generally considered safe, long-term risks in later adulthood remain unknown. There is particular concern with respect to cancer and cardiac events.

Dr Rogol agrees that the issue of growth-hormone efficacy in patients with ISS is controversial.

"Compared with a child with profound growth-hormone deficiency who will grow around 9 to 13 cm per year on treatment, someone with ISS may grow only around 6 cm per year, so efficacy may change adult height little, at a cost of US $20,000 to $40,000 annually."

On balance, he remarked, "If it means giving them 5 years of therapy, 365 injections a year at great cost for 4 to 5 cm of extra height, then these are relatively small changes."

Closer Appraisal of Decision Making Needed

Although the new findings do not justify a change in the guidelines for treating ISS, according to Dr Grimberg, she said that they do justify "a closer appraisal of how we behave in response to those guidelines."

According to a 2003 FDA approval of growth hormone for ISS, children whose height is at least 2.25 SD below the mean for age and gender are able to receive growth hormone without evidence of underlying disease.

Prior to this, children received growth hormone only for growth-hormone deficiency, affecting one in 3500 children; but now, one in 100 children are eligible to receive treatment, with a clear shift from diagnosis by pathophysiology to stature, she explained.

Dr Grimberg and her colleagues are currently studying factors that influence height-related medical decision making by parents and by primary-care pediatricians to better understand the underpinnings of the biases documented in their paper.

"Our ultimate goal is to develop interventions to eliminate or at least reduce disparities in the management of children and adolescents with short stature."

Dr Grimberg and the division of endocrinology and diabetes of the Children's Hospital of Philadelphia have been participating in the growth-hormone registries of all the major growth-hormone manufacturers. The authors have reported they have no relevant financial relationships. Dr Rogol has served as a consultant to Ammonett, SOV Therapeutics, Trimel Biopharmaceuticals, and Novo Nordisk.

Sci Rep. Published online June 9, 2015. Article

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